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Grand Challenges is a family of initiatives fostering innovation to solve key global health and development problems. Each initiative is an experiment in the use of challenges to focus innovation on making an impact. Individual challenges address some of the same problems, but from differing perspectives.

Because tuberculosis manipulates host cells to resist the immune response and current drug therapies, Nigel Savage of Leiden University Medical Center in the Netherlands will utilize RNAi analysis to identify the essential pathways used by the bacteria to modify its host cell. By discovering these pathways, novel therapies can be developed to counteract this host manipulation without directly targeting the pathogen and causing the development of resistance.

Oladele Akogun of the Common Heritage Foundation in Nigeria seeks to develop a “fever kit” for use among nomadic populations to help them accurately diagnose and treat fevers in a way that reduces mortality and drug resistance. The device will be equipped with simple diagnostic tools and prerecorded treatment instructions in the native language to help nomadic caregivers distinguish between malaria and other causes of fevers, and will also contain drug treatments appropriate to the diagnosed illness.

Boitumelo SemeteCouncil for Scientific and Industrial ResearchPretoria, South Africa

Grand Challenges Explorations

Drug Resistance

1 May 2009

To optimize the effectiveness of current anti-tuberculosis drugs, Boitumelo Semete of the CSIR in South Africa will work with collaborators to develop “sticky nanoparticles” that specifically attach to TB-infected cells. Once taken in by these cells, the nanoparticles will slowly degrade, releasing the anti-TB drugs and killing the bacteria. With this novel drug delivery system, the team aims to improve the bioavailability of the current therapies, with the possibility of shortening the treatment period for TB as well as reduce drug side effects.

Because DDT is the only insecticide that remains effective for more than a year, Walter Focke of the University of Pretoria in South Africa will investigate how insecticides degrade when applied on an indoor surface. Focke will then study whether combining the insecticide with paint to create a “whitewash” can mitigate this disintegration and enhance stability.

Maria Lerm of Linkoping University in Sweden will test her hypothesis that TB latency is a dynamic process in which a portion of the bacilli, when ingested by macrophages, trigger a genetic program where bacteria cycle between active and latent phases. Understanding whether this dynamic cycle exists could give new insights into maintaining or targeting the latent bacteria, which is the major reservoir of TB globally.

Reto Brun (Swiss Tropical and Public Health Institute) and Isabel Roditi (University of Bern) in Switzerland seek to identify small molecules that prematurely induce African trypanosomes, which are parasites that cause fatal sleeping sickness, to differentiate into the life stages necessary for transmission of the parasite. Forcing this transformation within the mammalian host could be the basis for new methods to kill trypanosomes, and this concept might be applied to other vector-borne disease . In this project’s Phase I research, Brun and Roditi developed a whole-cell assay to identify small molecules that stimulate early differentiation of African trypanosomes. In Phase II, they will perform high-throughput screens for such small molecules, validate active molecules in a suite of assays, and study them in a mouse model of infection.

Erich Cerny of Wissenschaftlicher Fonds Onkologie in Switzerland will test whether inducing antibodies against anti-malarial drugs can significantly prolong the half- life of that drug. Antibodies elicited via immunization may form a reservoir of the active drug for long-lasting treatment for malaria. Such a “small molecule vaccine” has significant implications for efficacy and cost of malaria prevention.

Melody Swartz and Jeffrey Hubbell of the Ecole Polytechnique Fédérale de Lausanne (EPFL), Switzerland, will explore the use of a robust and inexpensive nanotechnology, which may penetrate lymph tissue to more effectively trigger immune responses, as a new tool for prevention of TB.

Bongkoch Tarnchompoo of the National Center for Genetic Engineering and Biotechnology in Thailand will attempt to develop and test a novel drug that binds to the two pathways used by the DHFR enzyme in P. falciparum to mutate. By tethering these active sites, the dual-binding drug will suppress the development of resistance to anti-malarial drugs.

Luke Savage and Dave Newman led engineers at Exeter University in the United Kingdom in a program to develop a handheld, inexpensive battery-powered instrument that can rapidly diagnose malaria. By using magneto-optics to detect the hemozoin crystals produced as a byproduct of malaria parasite digestion of hemoglobin in the red blood cell, they avoid relying on invasive blood sampling. The project's Phase I research produced a robust hand-held diagnostic device able under laboratory conditions to detect malarial infection at well below 100 parasitized red blood cells per microliter in less than two minutes. In Phase II, simpler yet improved second generation devices will undergo further development and clinical testing under field conditions until they can meet the sensitivity and specificity standards required of a test for malaria.

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